Although inflammatory mediators such as bradykinin (iBK), prostaglandin E2 (iPGE2), leukotriene B4 (iLTB4), and substance P (iSP) have been proposed to contribute to several forms of orofacial pain and inflammation, most of our knowledge of these mediators is derived from pharmacology studies where the substance is injected at relatively high concentrations into peripheral tissue. Comparatively little is known about the actual levels and regulation of these mediators in clinical models of orofacial pain. An initial objective for this thesis research is to validate a novel method for collecting tissue samples of inflammatory mediators using microdialysis probes (3 KDa and 20 KDa cut-off) implanted into awake patients who simultaneously provide pain reports following the extraction of third molars. This method is used to measure several prototypic inflammatory mediators, define their time course of release, and determine their modulation by test drugs. This research approach permits mechanistic studies evaluating the release and actions of inflammatory mediators in clinical conditions involving tissue inflammation. To date, the thesis-related research has developed, validated, and determined clinical time-response curves for the local release of iSP, iBK, iPGE2, and iLTB4. Specific aims for this project are to: 1) Validate the novel application of microdialysis probes for collecting tissue samples of inflammatory mediators in post-operative patients who can simultaneously provide pain reports. 2) Determine whether the enhanced analgesic effects of pre-operative administration of an NSAID (ibuprofen and flurbiprofen) are due to increased suppression of cyclooxygenase activity. 3) Determine if NSAID-induced inhibition of cyclooxygenase results in increased activity of lipoxygenase. 4) Determine the effects of synthetic glucocorticoid (methylprednisolone) on tissue levels of inflammatory mediators. 5) Determine actions of inflammatory mediators for evoking release of iSP from surgical sites. Collectively, these studies will provide a biochemically-based, mechanistic approach for identifying those compounds which may activate and/or sensitize peripheral primary afferent fibers.